In a remarkable breakthrough, Dr. Hyun Kyoung Lee, an associate professor of pediatrics – neurology at Baylor College of Medicine and an investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, has unveiled a groundbreaking biological mechanism for myelin regeneration and repair.
Myelin, the protective sheath enveloping neuronal fibers, plays a pivotal role in ensuring rapid and accurate neurotransmission. Dr. Lee’s study, published in the Proceedings of the National Academy of Science, sheds new light on this vital process.
Understanding Myelin Regeneration
Myelin is primarily produced by glial precursor cells known as oligodendrocytes, which are among the most abundant cells in the nervous system. Damage or loss of the myelin sheath is a hallmark of various neurological diseases in both adults (such as multiple sclerosis) and infants (e.g., cerebral palsy) and is common following brain injuries.
The Wingless (Wnt) signaling pathway is a key regulator of oligodendrocyte development and myelin regeneration. Elevated Wnt levels in the white matter during certain diseased conditions and brain injuries hinder myelin production by keeping oligodendrocytes in a “stalled/quiescent state.”
Unveiling the Mystery of Daam2
Several years ago, Dr. Lee and her team discovered that the glial protein Daam2, a part of the Wnt signaling pathway, inhibits oligodendrocyte differentiation during development, as well as myelin regeneration and repair. However, the precise mechanisms governing this process remained enigmatic until now.
The Role of Phosphorylation
To comprehend how Daam2 inhibits myelination, the researchers first needed to understand the regulation of Daam2 itself. Through biochemical approaches, they uncovered that cells regulate Daam2 activity by phosphorylation – the addition of phosphate chemical groups that influence gene activation or deactivation. Remarkably, Daam2 phosphorylation had different effects on various stages of oligodendrocyte development.
In early stages, it accelerated the conversion of oligodendrocyte precursors into glial cells. However, in later stages, it slowed down their maturation and their capacity to produce myelin. Dr. Lee, a member of Baylor’s Dan L Duncan Comprehensive Cancer Center, conducted further analyses to identify protein CK2 as responsible for Daam2 phosphorylation.
CK2α’s Crucial Role
The subunit CK2α was found to interact with Daam2 in lab-cultured oligodendrocytes and phosphorylate it. Extensive research using laboratory-cultured oligodendrocytes and mouse models provided compelling evidence that CK2α promotes oligodendrocyte differentiation by phosphorylating Daam2.
In a neonatal hypoxic-injury animal model, CK2α-mediated Daam2 phosphorylation played a protective role in developmental and behavioral recovery following neonatal hypoxia, a type of brain injury seen in conditions like cerebral palsy. Additionally, it facilitated remyelination after white matter injury in adult animals.
A Promising Therapeutic Avenue
These findings have uncovered a novel regulatory connection between CK2α and Daam2 in the Wnt pathway, governing stage-specific oligodendrocyte development. This revelation offers exciting prospects for future therapies aimed at repairing and restoring myelin, potentially alleviating several currently untreatable neurological conditions, according to Dr. Lee.
The study’s first author, Chih-Yen Wang, is now an assistant professor at the National Cheng Kung University. Other contributors to the research include Zhongyuan Zuo, Juyeon Jo, Kyoung In Kim, Christine Madamba, Qi Ye, Sung Yun Jung, and Hugo J. Bellen, all affiliated with Baylor College of Medicine and/or the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital.
This work received support from grants provided by NIH/NINDS, the National Multiple Sclerosis Society, the Cynthia and Anthony G. Petrello Endowment, the Mark A. Wallace Endowment, and the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health for the BCM IDDRC Neurobehavior and Neurovisualization Cores. The GERM core at Baylor College of Medicine assisted in mouse line generation, while scRNA-sequencing was partially supported by the SCG core and GARP core
Original source: This information was Initially covered by Texaschildrens.